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Editor-in-Chief | The invention of the antibacterial drug of enzyme beauty is a milestone of modern medicine
.
However, with the inappropriate use of antimicrobial drugs, bacterial resistance has gradually evolved into one of the top 10 major threats to global public health
.
At present, the control of drug-resistant bacteria mainly relies on new antibacterial drug strategies
.
However, the discovery of new drugs is increasingly difficult
.
Therefore, trying to improve the bactericidal efficiency of existing antibacterial drugs has become an inevitable choice
.
Improving the bactericidal efficiency of existing antimicrobials must target major resistance mechanisms
.
The main mechanisms that have long been recognized include decreased cell membrane permeability, activation of multidrug efflux pumps, increased hydrolase activity, decreased target protein alterations, and antimicrobial drug binding
.
The former reduces the uptake of antibiotics by reducing the permeability of the cell membrane, which can be called a "rejection" drug resistance mechanism that "rejects" the uptake of extracellular antibiotics; the latter three cause intracellular antibiotics to fail through efflux, hydrolysis, and reduction of binding.
To the lethal concentration, it can be called "attenuated" resistance mechanism that "attenuates" the action of intracellular antibiotics
.
Since drug-resistant bacteria will inevitably reduce the uptake of antimicrobial drugs, "weakening" the drug resistance mechanism can only be carried out within the framework of "rejecting" the drug resistance mechanism; Attenuating the role of the "resistance mechanism" can effectively use existing antimicrobial drugs to kill drug-resistant bacteria
.
However, only some β-lactamase inhibitors that "weak" the drug resistance mechanism are currently in clinical use, and there is no significant progress in the research on the "rejection" drug resistance mechanism.
Control root cause
.
Therefore, creating strategies to harness existing antimicrobials to control resistance by promoting uptake is a major scientific question that urgently needs to be investigated
.
In response to this problem, the research group of Peng Xuanxian and Li Hui, the Bloomberg research group, the Zhang Tiantuo research group and the Chen Zhuanggui research group of the Third Affiliated Hospital of Sun Yat-sen University, and the Yang Tianci research group of the Zhongshan Hospital Affiliated to Xiamen University jointly carried out research on this problem.
.
A research paper titled Glutamine promotes antibiotic uptake to kill multidrug-resistant uropathogenic bacteria was published in Science Transnational Medicine on December 23, 2021, and found that exogenous glutamine can promote the efficient removal of clinically isolated multidrug-resistant uropathogenic bacteria by commonly used antibiotics.
drug bacteria, demonstrating that this promotion is attributed to exogenous glutamine increasing the uptake of antimicrobials much higher than that consumed by NDM-1 hydrolysis and efflux pump efflux, revealing that glutamine that increases this uptake The regulatory mechanism of the amide-inosine-CpxA/CpxR-OmpF metabolic regulatory axis
.
Finding ways to promote the uptake of antibiotics by drug-resistant bacteria is crucial for the effective control of drug-resistant bacteria, but how to promote their uptake remains unclear
.
Researchers believe that the metabolic state of an organism determines its biological phenotype, and changes in the metabolic state can cause changes in the biological phenotype
.
Therefore, a metabolomic study of multidrug-resistant uropathogenic Escherichia coli was carried out
.
Through the study of metabolic pathway enrichment and pattern recognition, it was found that the metabolic pathways of alanine, aspartate and glutamate were inhibited, and the significant down-regulation of glutamine was the most important metabolic feature of these pathogens.
Reprogramming molecules to reprogram multidrug-resistant metabolomes into antimicrobial-sensitive metabolomes reverse bacterial resistance, thereby promoting the bactericidal efficiency of existing antibiotics
.
The results showed that glutamine can promote β-lactams, aminoglycosides, quinolones and tetracyclines to kill β-lactamase-containing drug-resistant Escherichia coli; it can also promote ampicillin to clear multi-drug resistance.
Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Edwards lentus, Vibrio alginolyticus, Vibrio parahaemolyticus and their biofilms
.
In a mouse systemic infection model, glutamine combined with ampicillin was found to increase the survival rate of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae infections from 0-20% to 100%
.
These results suggest that glutamine can broadly promote the bactericidal efficacy of antibiotics
.
Interestingly, glutamine combined with ampicillin also slowed bacterial resistance to antimicrobials
.
The test found that the minimum inhibitory concentration (MIC) of ampicillin combined with and without glutamine on sensitive and resistant Escherichia coli in vitro for 30 generations was about the same as that without exogenous glutamine.
1/4-1/3 of the amide
.
After continuous passage in mice for 5 generations, the combination of exogenous glutamine with Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae was less effective against glutamine and ampicillin than the combination with exogenous glutamine.
Synergistic medication is more sensitive
.
These results suggest that glutamine can prevent the development of drug resistance
.
Pharmacokinetic studies were carried out using the standard strain ATCC35218 producing β-lactamase
.
Based on the concentration gradient of extracellular ampicillin and the action time, the effect of glutamine on bacterial intracellular ampicillin content (Vin), hydrolysis rate (Vh) and efflux rate (Ve) was determined
.
The results showed that glutamine can greatly increase the uptake of ampicillin, thereby overcoming the hydrolysis of β-lactamase and the excretion of the active efflux system, resulting in a significant increase in the intracellular ampicillin content of bacteria
.
These results indicate that the promotion of ampicillin uptake by glutamine is the main reason for improving the bactericidal efficiency of ampicillin
.
In order to explore the molecular mechanism of glutamine promoting the uptake of antibiotics, using stable isotope labeling non-targeted metabolomics, gene deletion and functional molecular replacement functional verification and other technical methods, it was found that the metabolic flow of glutamine mainly flows to purine biosynthesis, inosine.
is the most critical effector; protein interaction and phosphorylation analysis showed that inosine regulates the phosphorylation of the CpxA/R two-component regulatory system through direct interaction, promoting the expression of OmpF
.
These studies discovered the glutamine-inosine-CpxA/R-OmpF metabolic regulation axis and its role in reversing bacterial resistance, and further investigated the physiological effects of the corresponding gene knockout strains of antimicrobial-susceptible Escherichia coli by constructing verified on
.
Taken together, these findings are expected to accelerate the creation of effective methods to combat chronic, multidrug-resistant, lingering, and bacterial biofilm infections
.
The discovery that glutamine increases bactericidal efficiency by promoting antimicrobial uptake opens up a new avenue for the use of existing antimicrobials to control multidrug-resistant infections
.
At the same time, the result that glutamine delays bacterial drug resistance opens up a new direction for preventing bacterial drug resistance
.
The discovery has obtained national and US invention patents, and is cooperating with Guangdong Litai Pharmaceutical Co.
, Ltd.
to develop new drugs
.
Zhao Xianliang (PhD graduate of School of Life Sciences, Sun Yat-sen University in 2014), Chen Zhuanggui (The Third Affiliated Hospital of Sun Yat-sen University), Yang Tianci (Zhongshan Hospital Affiliated to Xiamen University), and Ming Jiang (postdoctoral fellow of School of Life Sciences, Sun Yat-sen University) are the co-authors of the research paper.
an author
.
Link to the original text: http://doi.
org/10.
1126/scitranslmed.
abj0716 Publisher: 11th Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author owns all legal rights, and violators will be prosecuted
.
.
However, with the inappropriate use of antimicrobial drugs, bacterial resistance has gradually evolved into one of the top 10 major threats to global public health
.
At present, the control of drug-resistant bacteria mainly relies on new antibacterial drug strategies
.
However, the discovery of new drugs is increasingly difficult
.
Therefore, trying to improve the bactericidal efficiency of existing antibacterial drugs has become an inevitable choice
.
Improving the bactericidal efficiency of existing antimicrobials must target major resistance mechanisms
.
The main mechanisms that have long been recognized include decreased cell membrane permeability, activation of multidrug efflux pumps, increased hydrolase activity, decreased target protein alterations, and antimicrobial drug binding
.
The former reduces the uptake of antibiotics by reducing the permeability of the cell membrane, which can be called a "rejection" drug resistance mechanism that "rejects" the uptake of extracellular antibiotics; the latter three cause intracellular antibiotics to fail through efflux, hydrolysis, and reduction of binding.
To the lethal concentration, it can be called "attenuated" resistance mechanism that "attenuates" the action of intracellular antibiotics
.
Since drug-resistant bacteria will inevitably reduce the uptake of antimicrobial drugs, "weakening" the drug resistance mechanism can only be carried out within the framework of "rejecting" the drug resistance mechanism; Attenuating the role of the "resistance mechanism" can effectively use existing antimicrobial drugs to kill drug-resistant bacteria
.
However, only some β-lactamase inhibitors that "weak" the drug resistance mechanism are currently in clinical use, and there is no significant progress in the research on the "rejection" drug resistance mechanism.
Control root cause
.
Therefore, creating strategies to harness existing antimicrobials to control resistance by promoting uptake is a major scientific question that urgently needs to be investigated
.
In response to this problem, the research group of Peng Xuanxian and Li Hui, the Bloomberg research group, the Zhang Tiantuo research group and the Chen Zhuanggui research group of the Third Affiliated Hospital of Sun Yat-sen University, and the Yang Tianci research group of the Zhongshan Hospital Affiliated to Xiamen University jointly carried out research on this problem.
.
A research paper titled Glutamine promotes antibiotic uptake to kill multidrug-resistant uropathogenic bacteria was published in Science Transnational Medicine on December 23, 2021, and found that exogenous glutamine can promote the efficient removal of clinically isolated multidrug-resistant uropathogenic bacteria by commonly used antibiotics.
drug bacteria, demonstrating that this promotion is attributed to exogenous glutamine increasing the uptake of antimicrobials much higher than that consumed by NDM-1 hydrolysis and efflux pump efflux, revealing that glutamine that increases this uptake The regulatory mechanism of the amide-inosine-CpxA/CpxR-OmpF metabolic regulatory axis
.
Finding ways to promote the uptake of antibiotics by drug-resistant bacteria is crucial for the effective control of drug-resistant bacteria, but how to promote their uptake remains unclear
.
Researchers believe that the metabolic state of an organism determines its biological phenotype, and changes in the metabolic state can cause changes in the biological phenotype
.
Therefore, a metabolomic study of multidrug-resistant uropathogenic Escherichia coli was carried out
.
Through the study of metabolic pathway enrichment and pattern recognition, it was found that the metabolic pathways of alanine, aspartate and glutamate were inhibited, and the significant down-regulation of glutamine was the most important metabolic feature of these pathogens.
Reprogramming molecules to reprogram multidrug-resistant metabolomes into antimicrobial-sensitive metabolomes reverse bacterial resistance, thereby promoting the bactericidal efficiency of existing antibiotics
.
The results showed that glutamine can promote β-lactams, aminoglycosides, quinolones and tetracyclines to kill β-lactamase-containing drug-resistant Escherichia coli; it can also promote ampicillin to clear multi-drug resistance.
Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Edwards lentus, Vibrio alginolyticus, Vibrio parahaemolyticus and their biofilms
.
In a mouse systemic infection model, glutamine combined with ampicillin was found to increase the survival rate of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae infections from 0-20% to 100%
.
These results suggest that glutamine can broadly promote the bactericidal efficacy of antibiotics
.
Interestingly, glutamine combined with ampicillin also slowed bacterial resistance to antimicrobials
.
The test found that the minimum inhibitory concentration (MIC) of ampicillin combined with and without glutamine on sensitive and resistant Escherichia coli in vitro for 30 generations was about the same as that without exogenous glutamine.
1/4-1/3 of the amide
.
After continuous passage in mice for 5 generations, the combination of exogenous glutamine with Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae was less effective against glutamine and ampicillin than the combination with exogenous glutamine.
Synergistic medication is more sensitive
.
These results suggest that glutamine can prevent the development of drug resistance
.
Pharmacokinetic studies were carried out using the standard strain ATCC35218 producing β-lactamase
.
Based on the concentration gradient of extracellular ampicillin and the action time, the effect of glutamine on bacterial intracellular ampicillin content (Vin), hydrolysis rate (Vh) and efflux rate (Ve) was determined
.
The results showed that glutamine can greatly increase the uptake of ampicillin, thereby overcoming the hydrolysis of β-lactamase and the excretion of the active efflux system, resulting in a significant increase in the intracellular ampicillin content of bacteria
.
These results indicate that the promotion of ampicillin uptake by glutamine is the main reason for improving the bactericidal efficiency of ampicillin
.
In order to explore the molecular mechanism of glutamine promoting the uptake of antibiotics, using stable isotope labeling non-targeted metabolomics, gene deletion and functional molecular replacement functional verification and other technical methods, it was found that the metabolic flow of glutamine mainly flows to purine biosynthesis, inosine.
is the most critical effector; protein interaction and phosphorylation analysis showed that inosine regulates the phosphorylation of the CpxA/R two-component regulatory system through direct interaction, promoting the expression of OmpF
.
These studies discovered the glutamine-inosine-CpxA/R-OmpF metabolic regulation axis and its role in reversing bacterial resistance, and further investigated the physiological effects of the corresponding gene knockout strains of antimicrobial-susceptible Escherichia coli by constructing verified on
.
Taken together, these findings are expected to accelerate the creation of effective methods to combat chronic, multidrug-resistant, lingering, and bacterial biofilm infections
.
The discovery that glutamine increases bactericidal efficiency by promoting antimicrobial uptake opens up a new avenue for the use of existing antimicrobials to control multidrug-resistant infections
.
At the same time, the result that glutamine delays bacterial drug resistance opens up a new direction for preventing bacterial drug resistance
.
The discovery has obtained national and US invention patents, and is cooperating with Guangdong Litai Pharmaceutical Co.
, Ltd.
to develop new drugs
.
Zhao Xianliang (PhD graduate of School of Life Sciences, Sun Yat-sen University in 2014), Chen Zhuanggui (The Third Affiliated Hospital of Sun Yat-sen University), Yang Tianci (Zhongshan Hospital Affiliated to Xiamen University), and Ming Jiang (postdoctoral fellow of School of Life Sciences, Sun Yat-sen University) are the co-authors of the research paper.
an author
.
Link to the original text: http://doi.
org/10.
1126/scitranslmed.
abj0716 Publisher: 11th Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author owns all legal rights, and violators will be prosecuted
.
